Clinical outcomes of pomalidomide‐based and daratumumab‐based therapies in patients with relapsed/refractory multiple myeloma: A real‐world cohort study in China

Abstract Background Comparative investigations evaluating the efficacy of pomalidomide‐based (Pom‐based) versus daratumumab‐based (Dara‐based) therapies in patients with relapsed/refractory multiple myeloma (RRMM) remain scarce, both in randomized controlled trials and real‐world studies. Methods This retrospective cohort study included 140 RRMM patients treated with Pom‐based or Dara‐based or a combination of pomalidomide and daratumumab (DPd) regimens in a Chinese tertiary hospital between December 2018 and July 2023. Results The overall response rates (ORR) for Pom‐based (n = 48), Dara‐based (n = 68), and DPd (n = 24) groups were 57.8%, 84.6%, and 75.0%, respectively (p = 0.007). At data cutoff on August 1, 2023, the median progression‐free survival (PFS) was 5.7 months (95% CI: 5.0–6.5) for the Pom‐based group, 10.5 months (5.2–15.8) for the Dara‐based group, and 6.7 months (4.0–9.3) for the DPd group (p = 0.056). Multivariate analysis identified treatment regimens (Dara‐based vs. Pom‐based, DPd vs. Pom‐based) and Eastern Cooperative Oncology Group performance status (ECOG PS) as independent prognostic factors for PFS. In the subgroups of patients aged >65 years, with ECOG PS ≥2, lines of therapy ≥2, extramedullary disease or double‐refractory disease (refractory to both lenalidomide and proteasome inhibitors), the superiority of Dara‐based regimens over Pom‐based regimens was not evident. A higher incidence of infections was observed in patients receiving Dara‐based and DPd regimens (Pom‐based 39.6% vs. Dara‐based 64.7% vs. DPd 70.8%, p = 0.009). Conclusions In real‐world settings, Pom‐based, Dara‐based, and DPd therapies exhibited favorable efficacy in patients with RRMM. Dara‐based therapy yielded superior clinical response and PFS compared to Pom‐based therapy.


| INTRODUCTION
Multiple myeloma (MM), as a plasma cell malignancy, remains largely incurable, and the majority of patients eventually progress to relapse and/or refractory MM (RRMM). 1 Within the past two decades, the availability of multiple novel therapeutic drugs has largely improved the outcomes of RRMM. 2 Pomalidomide (Pom) is a third-generation immunomodulatory agent, whose antimyeloma mechanisms mainly involve it binding to cereblon (CRBN), promoting the ubiquitination and degradation of IL-2 transcriptional repressors, Ikaros and Aiolos, and negatively regulating transcriptional factors IRF4 and MYC. 3 In 2013, Pom was approved for the treatment of patients with RRMM who had undergone at least two prior therapies, including lenalidomide and bortezomib. 4Daratumumab (Dara) is another representative drug that is widely available and used for the treatment of RRMM.As a human IgGκ monoclonal antibody, Dara directly targets the highly expressed CD38 antigen on plasma cells and induces their death.It also has immunomodulatory and immune-mediated effects. 5,6Dara has been approved for use as monotherapy or in combination with standard-of-care regimens for RRMM.
Following the approval of novel antimyeloma drugs and therapeutic combinations, the treatment paradigm for MM has rapidly evolved.Lenalidomide combined with bortezomib and a steroid has emerged as a predominant first-line treatment; hence, patients relapsed often have had prior exposure or become refractory to lenalidomide and/ or bortezomib. 7In the phase III OPTIMISMM trial, Pom combined with bortezomib and dexamethasone produced a median progression-free survival (PFS) of 11.2 months in patients previously exposed to lenalidomide (71% lenalidomide refractory). 8In the CASTOR and POLLUX trials, the PFS benefit conferred by Dara in combination with bortezomib/lenalidomide and dexamethasone over bortezomib/lenalidomide and dexamethasone alone was maintained in patients given prior lenalidomide or bortezomib treatment. 9,10The APOLLO trial assessed combinations of Dara, Pom, and dexamethasone (DPd) in patients who had received lenalidomide and a proteasome inhibitor (PI) (79% lenalidomide refractory, 47% PI refractory), and a median PFS of 12.4 months was reported. 11Based on the demonstrated benefits in RRMM patients, including those previously treated with or refractory to lenalidomide and/ or bortezomib, Pom-based, Dara-based, and DPd regimens have become prevalent salvage options after the failure of front-line therapies. 12ven with substantial evidence regarding specific regimens, the absence of comparisons between these regimens creates a challenge for physicians and patients in the treatment options for RRMM.Moreover, in view of the variation in baseline characteristics among patients, including age, frailty, comorbidities, disease biology, and treatment history, determining the optimal sequence and combination of drugs for distinct populations represents an outstanding clinical challenge.
This retrospective study reports the efficacy and safety of Pom-based, Dara-based, and DPd regimens for patients with RRMM in a single Chinese tertiary hospital.Comparisons were also made of the response and survival rates between these regimens across distinct subgroups.

| Study populations
This study was a single-centered, retrospective cohort study involving 140 patients at the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China, conducted between December 2018 and July 2023.The study inclusion criteria were as follows: age ≥18 years; diagnosis of MM based on International Myeloma Working Group (IMWG) criteria; the presence of measurable disease; 1-5 previous lines of therapy (LOT), and either relapsed or refractory to the last LOT; relatively complete clinical data; and completion of at least one cycle of Pom/Dara-based treatment.Patients with newly diagnosed MM, amyloidosis, primary plasma cell leukemia, or solitary plasmacytoma were excluded.Patients were divided into three groups based on the treatment namely a Pom-based group, a Dara-based group, and a DPd group.When patients received more than one of the aforementioned regimens successively, they were categorized based on the regimen first received.The follow-up endpoint was the date of the last follow-up or death through August 1, 2023.Their demographics, disease characteristics, and clinical outcomes were extracted from the hospital electronic medical records database after the approval of the review board.This research was approved by the institutional ethics committee of the First Affiliated Hospital of Zhejiang University School of Medicine.Data collection included patients' demographics, hematological disease characteristics, treatment history, treatment course, response, relapse, survival, and adverse events (AEs).

| Treatment
In this study, 48   S1.Supportive care (e.g., bone protection [bisphosphonate or denosumab], renal function protection [hydration and alkalization]), prophylaxis, and management of AEs were provided according to the physician's decision.

| Outcomes
The primary endpoints were PFS and the overall response rate (ORR).PFS was defined as the time from the initiation of Pom/Dara-based therapies to the date of PD or death.ORR was calculated as the proportion of patients who achieved at least a partial response.Secondary endpoints included overall survival (OS, the time from the initiation of Pom/Dara-based therapies to the date of death from any cause), time to next treatment (TTNT, the time from the initiation of Pom/Dara-based therapies to the date of initiating the next line of antimyeloma treatment or the date of death), and safety (AEs).Hematological responses were evaluated according to IMWG response criteria.High-risk cytogenetics was defined as the presence of del(17p), high-risk IgH translocation [t(14;16) or t(14;20)], or amplification of 1q using fluorescence in situ hybridization (FISH).Minimal residual disease (MRD) was detected by multicolor flow cytometry at a threshold of 1 tumor cell per 10 4 -10 5 white cells.AEs were assessed using the National Cancer Institute's common terminology criteria for adverse events (CTCAE) version 5.0.Efficacy assessments were conducted every 1-2 cycles or if a suspected relapse occurred.Optimal response data were considered as the outcome.Dose adjustments/ interruptions and their causes during treatment were carefully recorded, and AEs were monitored throughout the treatment cycles.

| Statistical analysis
Categorical variables are given as numbers and percentages (n, %) and comparisons made between groups using a chi-squared test or Fisher's exact probability test, as appropriate.Continuous variables are presented as the median and range (median, range), and nonparametric tests were applied to look for differences between groups.Time-to-event data were analyzed using the Kaplan-Meier method and described by the median time-to-event and 95% confidence intervals (median, 95% CI).Time to follow-up was estimated by the reverse Kaplan-Meier method.Patients who were lost to follow-up were censored from the date of their final follow-up.Differences between groups were evaluated using log-rank tests.Univariate and multivariate logistic regression and Cox regression models for ORR and PFS were built to improve the balance of confounders between groups.Only covariates with p < 0.1 were entered into the multivariate model.The results are shown as an odds ratio (OR) or hazard ratio (HR) with 95% CIs.Exploratory subgroup analysis and interaction tests were performed for ORR and PFS, stratified by age, extramedullary infiltration, the international staging system (ISS) stage, cytogenetics, renal function, Eastern Cooperative Oncology Group performance status (ECOG PS), prior LOT and refractory status to lenalidomide, PI, and both lenalidomide and PI (double-refractory).The results are presented as a risk ratio (RR) and HR with 95% CIs.Two-sided p ≤ 0.05 was considered to be a statistically significant difference.Data analyses were performed using GraphPad Prism ver.9.0 (GraphPad Software, San Diego, CA, USA) and SPSS ver.26.0 (SPSS, IBM Corp., Armonk, NY, USA).

| Baseline characteristics and treatment history of patients
The median age of our cohort was 63.5 years (range: 40-90), and 67/140 (47.9%) of the patients were identified as having high-risk cytogenetics.Patients had received a median of 2 (1-5) LOTs before initiating Pom/Darabased therapies.Most had been previously treated with lenalidomide or PIs (87.1% and 100%), and the proportion of patients refractory to lenalidomide, PI or both lenalidomide and PI was 72.1%, 70.0%, and 51.4%, respectively.The baseline characteristics and treatment history of patients are shown in Tables 1 and 2. A higher proportion of patients in the DPd cohort were refractory to PI compared to the other cohorts (p = 0.03).Other baseline and prior treatment characteristics were similar across the three treatment groups.
To identify differences based on treatment outcomes, we performed univariate and multivariate analyses for ORR and PFS (Table 3 and Table S3).After adjusting for baseline confounders with p < 0.1 (ECOG PS and lenalidomide-refractory status), treatment regimens (Dara-based vs. Pom-based, DPd vs. Pom-based) and ECOG PS remained as independent predictors for PFS.In the multivariate model for ORR, no covariates with p < 0.1 were entered (Table S3).
The results of post hoc subgroup analysis of PFS and ORR based on important clinical characteristics are summarized in Figure 3. Due to the small sample size, subgroup analysis was not performed for the DPd group.In the comparison of the Dara-based and Pom-based groups, a consistent improvement in the overall response was observed in most subgroups, especially in patients who were aged under 65 years, without extramedullary infiltration, at ISS stage of III, ECOG PS of 0-1, non-double-refractory, and first relapse (Figure 3A).Moreover, patients in several subgroups showed a PFS improvement, including those ≤65 years, without extramedullary disease, at ISS stage I and II, without renal insufficiency, at ECOG PS of 0-1, first relapse, and who were not PI, lenalidomide or double-refractory (Figure 3B).

| DISCUSSION
The efficacy of Pom combination drug regimens has been extensively evaluated through numerous randomized controlled trials (Table 5).A meta-analysis of 35 phase 2 and 3 clinical trials that involved Pom-based doublet and triplet regimens, majorly including Pom/low-dose dexamethasone (LoDex), bortezomib + Pom/LoDex, Dara + Pom/LoDex.The pooled data showed an ORR of 47.1% across all Pom-based regimens. 36Real-world studies in the United Kingdom, 37 Poland, 38 India, 39 and Greece 40 also reported the promising clinical effectiveness of Pom-based regimens, with ORR ranging from 39.1% to 58.7% and the median PFS ranging from 5.2 months to 10.5 months.Our cohort represents a real-world Chinese patient population, most of whom had previous treatment (87.1% and 100%) and were refractory (72.1% and 70.0%) to lenalidomide or PIs.An ORR of 57.8% and median PFS of 5.7 months were identified when Pom-based regimens were administered after a median of two lines of treatment, a finding in good agreement with prior publications.Previous studies revealed encouraging clinical outcomes of Dara-based regimens (Table 5).Results of the pivotal phase III CASTOR and POLLUX studies reported an ORR of 85% and 93%, 19,22 respectively, remarkably similar to the observed ORR (84.6%) of the Dara-based cohort in the present study.However, a relatively inferior median PFS was observed compared to previous trials (10.5 vs. 16.7 months in CASTOR and 45.8 months in POLLUX). 19,22This can partly be attributed to biases in population selection between the real-world context and clinical trial settings.In comparison with our cohort, in which a substantial proportion of patients exhibited treatment refractoriness, patients refractory to PI and lenalidomide were systematically excluded in the CASTOR and POLLUX studies, with the proportions of lenalidomide-refractory and bortezomib-refractory patients at merely 24% and 20.6%, respectively. 19,22The extended PFS of the nonlenalidomide-refractory subgroup of the Dara-based cohort further validates this explanation (median PFS of 23.9 months).Moreover, the high frequency of dose interruptions (45.6%) in clinical practice potentially attenuated the durability of efficacy.In comparison, a real-world study from the Mayo Clinic observed worse outcomes (ORR 47%, median PFS of 5.5 months) of Dara combination therapies in a heavily pretreated MM patient population (median LOT of 4). 41Nevertheless, our study, despite discrepancies with clinical trial outcomes, indicated that Dara-based regimens maintained promising efficacy in this Chinese real-world patient cohort.
Pom-based and Dara-based regimens have become common treatment options after the failure of front-line lenalidomide-based therapy.However, to the best of our knowledge, there has been a paucity of comparisons made between Pom-based and Dara-based regimens for RRMM in either clinical trials or real-world settings.The present research is the first retrospective cohort study that has compared these two drugs in a real-world context.On the basis of well-balanced baseline characteristics, the study showed that Dara-based regimens yielded a superior overall response (84.6% vs. 57.8%,p = 0.002) and ≥VGPR rate (41.5% vs. 15.6%,p = 0.004) compared to Pom-based regimens.Dara-based regimens were also associated with PFS benefit in the multivariate analysis (HR: 0.46, 95% CI: 0.27-0.79).T A B L E 5 (Continued) However, the results of exploratory subgroup analysis indicated that in patients characterized by poor prognostic features (double-refractory, multiple relapses [LOT ≥ 2], advanced age, ECOG PS ≥ 2, with extramedullary infiltration), the superiority of Dara-based therapy was not apparent.In a real-world study conducted at two centers in the United States that involved 299 patients, a decreasing response rate to Dara with later LOT was observed (1 L 100.0%, 2 L 78.8%, 3 L+ 65.2%). 42A retrospective cohort study from the Canadian Myeloma Research Group database (CMRG-DB) noticed a similar trend of prognosis (median PFS: 2 L 23.5 months, 3 L 12.8 months, 4 L 7.0 months) in 583 MM patients. 43Our results, expanding on previous findings, lend support to the hypothesis that administering optimal treatment regimens such as Darabased combinations, in the early stage of MM, rather than administering them later, may increase clinical benefit.Indeed, evidence from clinical trials also reflects this notion.The results of CASTOR and POLLUX showed the addition of Dara at first relapse greatly reduced the risk of PD or death by 81% and 58%, respectively. 9,10By far, Darabased regimens have been recommended as salvage therapy at first relapse by IMWG, 44 National Comprehensive Cancer Network (NCCN) 45 and mSMART guidelines. 46owever, due to the nonrandomized approach, this finding should be interpreted with caution, and head-to-head comparisons are still warranted for selecting the optimal treatment sequence.
Moreover, we have also presented the clinical data of 24 patients receiving DPd regimens in our hospital.A median PFS of 6.7 months (95% CI: 4.0-9.3)was reported, which is shorter than the PFS previously reported in clinical trials (12.4 months in APOLLO, 8.8 months in EQUULEUS, and 30.8 months in MM-014) (Table 5). 11,33,34Unlike these clinical trials, our cohort reflects a real-world unselected patient population, which includes a higher proportion of frail patients (ECOG PS ≥ 2: 37.5% vs. 4% in APOLLO) and patients with refractory status (PI-refractory: 91.7% vs. 47% in APOLLO). 11Despite the failure to observe the response superiority of DPd over Pom-based therapy (ORR: 75.0% vs. 57.8%,p = 0.16; ≥VGPR: 33.3% vs. 15.6%,p = 0.09), there was a PFS improvement in the multivariate model (HR: 0.48, 95% CI: 0.24-0.95).This finding suggests the addition of Dara into Pom and dexamethasone regimens may provide prognostic benefit compared to other combination therapies.It is worth noting that this DPd cohort represents a single-center cohort with a relatively small sample size, which may introduce certain biases in estimating outcomes.
Notably, in the treatment groups containing Dara (Dara-based and DPd), higher rates of infection were reported.Data from a number of randomized clinical trials also found the addition of Dara to PIs/immunomodulatory drugs increases the risk of infection (upper respiratory tract infection: from 14% to 44% and 23% to 63%), [9][10][11]25,47 which might be attributable to the immunoparesis induced by the CD38 receptor downregulation and the depletion of CD38-expressing immune cells. 48 Ouresults highlight the need to optimize monitoring, prophylaxis and supportive care in clinical practice for Dara-related infections.
This research is limited by its single-center retrospective design.However, the baseline characteristics were generally balanced between the patient groupings, and multivariate analyses and subgroup analyses were undertaken to mitigate potential bias.Due to the recent approval of Pom and Dara in China, the sample size was relatively small.The relatively small sample size, particularly in certain subgroups such as LEN-non-refractory and DPd groups, may have limited the statistical power to detect subtle differences or associations.The dosage and drugs used were not uniform, which might have impacted the evaluation of clinical outcomes.Some patients were followed-up in the outpatient setting, which may have resulted in loss of information.In addition, we failed to make a robust assessment of OS because of the short follow-up time.
Nevertheless, this study provides valuable real-world comparative information between Pom-based, Darabased, and DPd regimens for the treatment of RRMM populations.Considering the limitations of retrospective studies, more well-designed multicenter randomized clinical trials with larger sample sizes are highly anticipated to guide clinical decision-making.

| CONCLUSIONS
Pom-based, Dara-based, and DPd therapies had favorable clinical efficacies in patients with RRMM.Dara-based regimens were associated with improved outcomes compared to Pom-based therapies, albeit the superiority was not evident among patients with poor prognostic features.The DPd regimen also led to prolonged PFS compared to Pom-based therapies.Concerning safety, Dara-related infections warrant greater emphasis in clinical practice.

Conclusions:
In real-world settings, Pom-based, Dara-based, and DPd therapies exhibited favorable efficacy in patients with RRMM.Dara-based therapy yielded superior clinical response and PFS compared to Pom-based therapy.K E Y W O R D S daratumumab, multiple myeloma, pomalidomide, recurrence, refractory | 3 of 15 HAN et al.
Adverse events during treatment.
T A B L E 4